UV Irradiation Induces a Non-coding RNA that Functionally Opposes the Protein Encoded by the Same Gene

The transcription-related DNA damage response was analyzed on a genome-wide scale with great spatial and temporal resolution. Upon UV irradiation, a slowdown of transcript elongation and restriction of gene activity to the promoter-proximal ∼25 kb is observed. This is associated with a shift from ex...

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Veröffentlicht in:Cell 2017-02, Vol.168 (5), p.843-855.e13
Hauptverfasser: Williamson, Laura, Saponaro, Marco, Boeing, Stefan, East, Philip, Mitter, Richard, Kantidakis, Theodoros, Kelly, Gavin P., Lobley, Anna, Walker, Jane, Spencer-Dene, Bradley, Howell, Michael, Stewart, Aengus, Svejstrup, Jesper Q.
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Sprache:eng
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Zusammenfassung:The transcription-related DNA damage response was analyzed on a genome-wide scale with great spatial and temporal resolution. Upon UV irradiation, a slowdown of transcript elongation and restriction of gene activity to the promoter-proximal ∼25 kb is observed. This is associated with a shift from expression of long mRNAs to shorter isoforms, incorporating alternative last exons (ALEs) that are more proximal to the transcription start site. Notably, this includes a shift from a protein-coding ASCC3 mRNA to a shorter ALE isoform of which the RNA, rather than an encoded protein, is critical for the eventual recovery of transcription. The non-coding ASCC3 isoform counteracts the function of the protein-coding isoform, indicating crosstalk between them. Thus, the ASCC3 gene expresses both coding and non-coding transcript isoforms with opposite effects on transcription recovery after UV-induced DNA damage. [Display omitted] •UV elicits elongation slowdown and restricts transcription to the 5′ end of genes•UV induces a switch from long to short alternative last exon (ALE) transcript isoforms•ASCC3 short and long ALE isoforms have antagonistic functions in the UV response•The UV-induced ASCC3 short isoform functions as a long non-coding RNA UV damage generates a functional non-coding RNA through alternative pre-mRNA processing of a damage response factor transcript, identifying a pathway for repurposing protein coding genes under selective conditions.
ISSN:0092-8674
1097-4172
1097-4172
DOI:10.1016/j.cell.2017.01.019